arXiv subjects

Pablo Gottheil

Publications and source records attributed to Pablo Gottheil.

3 recordsLinked to original sources

arXiv2026

Nuclear mechanics controls the temporal dynamics of cell unjamming

Cell unjamming in dense tissues is a complex but essential process in embryogenesis and cancer metastasis. Increasing evidence suggests that nuclear mechanics and density effects play a vital role in collective cell unjamming. However, state-of-the-art cell-shape-based theories fail to include nuclear and density effects, while computer models featuring rigid nuclei disagree with experimental observations of elongated nuclei promoting unjamming. Here, we introduce a computational model of confluent cells with explicitly deformable nuclei to study the dynamics of cell unjamming. Our simulations show an unjamming transition controlled by nuclear size and shape, reconciling conflicting theories of density-driven versus shape-driven mechanisms. We predict general relations connecting cellular and nuclear shape to collective cell motion, verified experimentally in distinct monolayers of MCF-10A and MDA-MB-436 breast cells, with striking accuracy. Our work establishes a rational connection between nuclear mechanics and tissue-scale rigidity transitions, highlighting the nucleus's key role in collective cell unjamming.

physics.bio-ph↗

arXiv2024

Self organisation of invasive breast cancer driven by the interplay of active and passive nematic dynamics

In invasive breast cancer, cell clusters of varying sizes and shapes are embedded in the fibrous extracellular matrix (ECM). Although the prevailing view attributes this structure to increasing disorder resulting from loss of function and dedifferentiation, our findings reveal that it arises through a process of active self-organization driven by cancer cell motility. Simulations and histological analyses of tumours from over 2,000 breast cancer patients reveal that motile, aligned cancer cells within clusters move as active nematic aggregates through the surrounding highly aligned ECM fibres, which form a confining, passive nematic phase. Cellular motion leads to cluster splitting and coalescence. The degree of cluster activity, combined with heterogeneity in cell motility, is reflected in specific scaling behaviours for cluster shape, size distribution, and the distance between cluster boundaries and nematic defects in ECM alignment. Increased activity estimates correlate with tumour progression and are associated with a poorer prognosis for patients.

physics.bio-ph↗

arXiv2022

Prognostic relevance of gene-expression signatures

Cancer prognosis can be regarded as estimating the risk of future outcomes from multiple variables. In prognostic signatures, these variables represent expressions of genes that are summed up to calculate a risk score. However, it is a natural phenomenon in living systems that the whole is more than the sum of its parts. We hypothesize that the prognostic power of signatures is fundamentally limited without incorporating emergent effects. Convergent evidence from a set of unprecedented size (ca. 10,000 signatures) implicates a maximum prognostic power. We show that a signature can correctly discriminate patients' prognoses in no more than 80% of the time. Using a simple simulation, we show that more than 50% of the potentially available information is still missing at this value.

physics.bio-ph↗